Background
Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequent and pejorative in patients with paragangliomas. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to detect succinate in vivo by magnetic resonance spectroscopy (1H-MRS).
Method
A 1H-MRS sequence was optimized and applied to image nude mice grafted with Sdhb-/- (n=13) or wild-type chromaffin cells (n=16). The method was then applied in a pilot study to 9 patients with paragangliomas carrying (n=5) or not (n=4) an SDHx gene mutation and further validated in another 26 patients enrolled prospectively in the radiology department of the Georges Pompidou Hospital in Paris. Following surgery, succinate was measured using GC-MS/MS in resected tumors.
Results
In the pilot study1, a succinate peak was observed at 2.44 ppm by 1H-MRS in all Sdhb-/--derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients without SDHx mutation. 1H-MRS results led to the identification of an unsuspected SDHA gene mutation and helped defining the pathogenicity of a variant of unknown significance in the SDHB gene. The ongoing validation study has already evaluated 26 patients (9 with an SDHx mutation, 1 VHL, 8 sporadic and 8 more patients with genetic pending results). This study revealed an estimated sensitivity and specificity of the 1H-MRS of 71 and 92%, respectively.
Conclusions
This noninvasive approach is a new, simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. The precise analysis of tumor size, location and mutation types will allow defining the limits and the power of this innovative method for routine imaging diagnosis.